A Day in the Life of a Breast Cancer Doctor: Integrating Omics to Optimize Patient Outcomes. March 17-18, 2015 New York, NY

Transcription

1 A Day in the Life of a Breast Cancer Doctor: Integrating Omics to Optimize Patient Outcomes March 17-18, 2015 New York, NY

2 A Day in the Life of a Breast Cancer Doctor: Integrating Omics to Optimize Patient Outcomes Moderator: Otis Webb Brawley, MD, FACP, Chief Medical and Scientific Officer, Executive Vice President, Research, American Cancer Society Panelists: Brad Gray, President & CEO, NanoString Technologies, Inc. Amy Krie, MD, Medical Oncology and Hematology, Avera Cancer Institute Manfred Lehnert, MD, VP and Head, Innovation, Oncology Therapeutic Area Unit, Takeda Pharmaceuticals International Co. Brian Leyland-Jones, MB BS, PhD, VP, Molecular and Experimental Medicine, Avera Cancer Institute John J. Sninsky, PhD, Chief Scientific Officer, CareDX 2

3 Cancer Treatment Eras Era 1: Local-regional therapy Era 2: Nonspecific systemic therapy Era 3: Targeted therapy Era 4: The Genome Era

4 There Is An Increasing Shift Toward Targeted Therapy In Cancer Chemotherapy Targeted Therapy Anticancer drugs may be highly effective in some, but less effective in others Patients are exposed to the risk of side effects In personalized medicine, clinicians use biomarkers to predict a patient's response to therapy Patients are more likely to get therapies with the greatest impact with fewer side effects 4 4

5 Identifying Tumor Genomic Alterations that Indicate Therapies Dancey et al. Cell 148; 2012

6 The Genomic Era

7 The Genome Era First human genome: 2001 First cancer genomes: 2009 Large-scale sequencing: NOW Population-based sequencing: SOON

8 Conventional Cancer Treatment Patient s tissue sample pathology grade, size, IHC Chemotherapy Personalized cancer treatment Patient s tissue sample Molecular diagnostics P P P P P P P P P P P P P P P P P Pathway targeted (combination)therapy which pathways are active?

9 Frequency (%) of Mutations In Common Cancers Tumor Type Braf Kras EGFR PIK3CA NRAS ckit GNA1 1 GNAQ /GNAS Lung & Bronchus Colon Pancreatic Melanoma & GE/Gastric Kidney 2* 1* 0 4* Leukemia & Lymphoma 1* 3* 4* 0 6* Prostate * 2* 2* 0 0 Breast Ovarian Mutations determined by Cobas, Sanger, and /or Illumina NGS *n 100 & Ascierbo et al Lancet, 14:249-56, 2013 Gatalica et al. ASCO 2013

10 Likelihood of Response by Extent of Prior Treatment* Probability of Response By Line of Therapy 70% 60% 50% 40% 30% 20% 10% 0% Number of Prior Regimens Probability of Response patients who benefit from chemotherapy (in the metastatic setting) may be treated successfully with other regimens at the time of progression. However, the chance of response decreases by about half with each subsequent treatment. DeVita VT. Cancer Prin & Prac of Oncol, 5th Edition, pp *Graph was NOT taken from DeVita but is provided to illustrate the effects of the quote above and assumes an initial response of 60%.

11 FORWARD GENOMIC ONCOLOGY Tumor Biopsy >60% tumor Sequencing Tumor Board Informed Consent & Genetic Counselor Sequencing & Analysis 1) Actionable 2) Incidental Buccal swab or Blood (germline) Genetic Counselor Disclosure of Results

12 PLATFORMS At all 3 timepoints (first 2 only if pcr): 1. Foundation Medicine 2. RNA Seq 3. Theralink 4. WGS 5. Central Ki67 6. HRD assay (to be included in Nanostring) 7. NANOSTRING a) PanCancer Pathways b) CNV c) Fusion d) Immunology 8. CTC s and cfdna

13 A 38-year-old man with BRAF-mutant melanoma and miliary, subcutaneous metastatic deposits, treated with PLX4032 (Vemurafenib). Baseline 15 weeks 23 weeks Wagle N et al. JCO 2011;29:

14 Blue: Downregulated & CNV: Loss / Red: Upregulated & CNV: Gain Yellow/Red text: Tumor 1 Drug Targets Yellow/Black text: Tumor 2 Drug Targets

15 Recommended Treatment SEQUENCING PROGRESS NOTE History of present illness: Wanda is a 71 y/o with history of stage IIIC ovarian cancer. Treatment Recommendations: AKT2 amplication- no approved therapies. Clinical trials of Akt inhibitors for various tumor types. mtor inhibitors everolimus and temsirolimus are FDA approved for other indications. PIK3CA mtor inhibitors everolimus and temsirolimus are FDA approved for other tumor types. Associated with resistance to Egfr-targeted therapies. CCNE1 amplification primary resistance to platinum-based treatment in patients with ovarian carcinoma. MYC amplification Preclinical evidence suggests may be more sensitive to 5- fluorouracil (5fu) and paclitaxel. Our treatment recommendation for this patient would be Taxol +/- 5Fu with Everolimus. We thank you again for the referral and working with us. Sincerely, Dr. Brian Leyland-Jones and team Avera Medical Group Genomic Medicine

16 GENOMIC MEDICINE: OUR TEAM S MANTRA 1. MULTIPLATFORM* 2. COMBINATIONS OF THERAPIES (SOME OF WHICH HAVE NEVER BEEN COMBINED BEFORE): N OF ONE* 3. SHIFT TO EARLY TREATMENT 4. THE NEXT GENERATION OF CUTTING EDGE THERAPIES ARE ALL IN CLINICAL TRIALS: BUILDING THE DRUG UMBRELLA* 5. REGULATORY AUTHORITIES* 6. RE-EDUCATION..NCCN GUIDELINES 7. INSURANCE COVERAGE: TESTING/ DRUGS Patients that live longer cost more

17 K.A.K. History ER+ PR+ Her2-5/2002 diagnosed with Stage III ER/PR+ HER2- IDC of left breast, had modified radical mastectomy followed by radiation. 1/ /2005 on tamoxifen 11/2005-2/2012 transitioned to Aromasin 2/2012-7//2012 progression in lymph nodes and bones, biopsy shows ER 25% PR 0% Her 2 by IHC 2+, FISH ratio 1.1. Changed therapy to faslodex. 7/2012-6/2013 progression in LN s and bone changed to Xeloda 6/ /2013 progression in LN s and bone changed to Letrozole and afinitor complicated by pneumonitis and progression in bone. 12/2013-2/ weeks of Taxol with no response. 3/2014 bone biopsy for sequencing, pathology shows ER 50% PR 0% HER 2 by IHC 3+. 4/2104-9/2014 therapy changed to carboplatin, herceptin and perjeta. 9/2014 progression in bone and LN s: referral to MEM for genomic profiling

18 K.A.K. Therapeutic Implications Genomic Alterations Detected FDA Approved Therapies (in patient s tumor type) FDA Approved Therapies (in another tumor type) Potential Clinical Trials MYC Amplification equivocal GATA3 I36fs*10, P409fs*38+ None None Yes None None None

19 K.A.K. FoundationOne from metastatic lymph node in 2012

20 K.A.K. Theralink from metastatic lymph node in 2012

21 K.A.K. Basis for Recommendations COMPLETE BLOCKAGE OF ALL PATHWAYS: CRITICAL. Aggressive disease: add taxol, even though had not responded before! Now Her2 3+: treat with Trastuzumab, even though had not responded before! (Also has pher3 3+ on Theralink) mtor I1973F (FO) + pmtor (Theralink): treat with Everolimus FGF 19, FGF 4, FGF 3 amplifications: treat with Pazopanib

22 K.A.K. Treatment 11/6/14: Weekly paclitaxel 80 mg/m2. Herceptin 6mg/kg. Everolimus 2.5mg qd. Pazopanib 200mg qd. Anastrazole.

23 2/7/12 2/4/15 25

24 K.A.K. Outcomes 2/4/15 CT shows all previous sites of active metastatic adenopathy in both mediastinum and hilar regions in the chest are no longer evident. No other sites of active macroscopic neoplastic-metastatic disease. Grade 2 fatigue and rash.

25 Challenges of Genomics in Oncology from the Clinical Perspective Shift from standardized to tailored paradigm Shift to increased use of oral chemotherapy Cost more Increased patient and staff education Drug reimbursement Changing role of the pathologist Repeat biopsy for evolving tumor liquid biopsy

26 A Day in the Life of a Breast Cancer Doctor: Integrating Omics to Optimize Patient Outcomes Moderator: Otis Webb Brawley, MD, FACP, Chief Medical and Scientific Officer, Executive Vice President, Research, American Cancer Society Panelists: Brad Gray, President & CEO, NanoString Technologies, Inc. Amy Krie, MD, Medical Oncology and Hematology, Avera Cancer Institute Manfred Lehnert, MD, VP and Head, Innovation, Oncology Therapeutic Area Unit, Takeda Pharmaceuticals International Co. Brian Leyland-Jones, MB BS, PhD, VP, Molecular and Experimental Medicine, Avera Cancer Institute John J. Sninsky, PhD, Chief Scientific Officer, CareDX 28